Two clinical trials are presently underway as part of this project.[unreadable] [unreadable] The first clinical trial is a single-center randomized, double-blinded, placebo-controlled study involving 170 diabetic Pima Indian adults with normal urinary albumin excretion or microalbuminuria. It was designed to determine whether blockade of the angiotensin II receptor with losartan will prevent or further attenuate the development and progression of early diabetic nephropathy in subjects with type 2 diabetes mellitus who are receiving standard diabetes care that now includes treatment with the angiotensin converting enzyme inhibitor lisinopril. Subjects in each albumin excretion group were randomized to treatment with either losartan, or placebo. Measurements of glomerular filtration rate, renal plasma flow and fractional clearances of albumin and IgG were made using standard urinary clearance methods as outlined in Project Number Z01 DK069063-12. These tests were performed initially, at one month, and at 12-month intervals from baseline thereafter. The primary outcome measure is a decline in GFR to less than 60 ml/min or to half the baseline value in subjects that enter the study with a GFR of <120 ml/min. A kidney biopsy was performed after 5.5 years in 120 of these subjects. Morphometric analysis of kidney biopsies, as reported in Project Number Z01 DK069100-01, will be used to determine differences in the prevalence of global sclerosis, the number of visceral epithelial cells per glomerulus, and the breadth of epithelial foot processes between treatment groups. Differences in a severity index computed from the joint distribution of these morphometric variables will be used to assess the renoprotective efficacy of losartan at the tissue level. Following the kidney biopsy and after the 72-month renal clearance study, treatment with all ACEi and ARBs will be stopped for six weeks. At the end of the six-week washout period a second clearance study will be performed. Randomized study treatment will end at that time, but quarterly follow-up visits and annual renal clearance studies will continue to the onset of kidney failure. This project, in part, represents extensions of work previously reported as Project Number Z01 DK69037.[unreadable] [unreadable] The second clinical trial is a multicenter randomized, double-blinded, placebo-controlled study involving approximately 2358 in adults with type 2 diabetes and chronic kidney disease. Participants will be enrolled over a two-year period in approximately 200 centers worldwide. All subjects will be treated with either irbesartan 300 mg/day or losartan 100 mg/day. Patients will be randomized to treatment with either sulodexide 200 mg/day or a placebo of identical appearance. Treatment will continue for two years after the recruitment period and patients will be followed at three-month intervals during treatment. The primary outcome measure is the increase in time to the first occurrence of the composite endpoint of a doubling of the serum creatinine concentration from baseline or end-stage renal disease.[unreadable] [unreadable] In the past year, we completed the randomized portion of the losartan clinical trial and are presently completing the laboratory assays of glomerular filtration rate and renal plasma flow. We are performing morphometric analyses on the kidney biopsies as described in Project Number Z01 DK069100-01. Portions of the kidney tissue from each patient are undergoing laser microdissection to separate the tubular and glomerular components, and gene expression studies are being conducted on these tissues and results of these expression studies will be correlated with the appearance of various urinary biomarkers. The sulodexide clinical trial was initiated in the past year and recruitment will continue into the coming year. These projects are expected to yield new insights into the management of kidney disease in type 2 diabetes.